Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to ...fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. We look at new approaches to unravelling the complex virus–host interactions that lead to persistent infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV.
Among the different markers of HIV persistence in infected cells, total HIV DNA is to date the most widely used. It allows an overall quantification of all viral forms of HIV DNA in infected cells, ...each playing a different role in HIV replication and pathophysiology. The real-time PCR technology is to date, a precise, sensitive and reproducible technology that allows the description of the distribution of HIV infected cells in blood and tissues. The objective of this review is to present some examples which show the interest to quantify total HIV DNA levels. This marker brought an undeniable and considerable contribution to reservoir studies. Many results, both in clinical and basic research, allowed to get a large overview of the distribution of infected cells in the body, at all stages of HIV disease and during therapy. Future clinical studies aiming at reducing HIV reservoirs will benefit from HIV DNA quantification in blood and tissues, in association with other markers of HIV reservoir activity.
Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity; however, HIV can still not be cured. Achieving either a functional cure (long-term ...control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV-infected cells) remains a major challenge. The most significant barrier to cure is the establishment of a latent or 'silent' infection in resting CD4 T cells. Several randomized clinical trials have demonstrated that treatment intensification with additional antiretrovirals has little impact on latent reservoirs. Some potential other approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could reverse latent infection. Drugs such as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers; methylation inhibitors; cytokines such as IL-7 or activators of nuclear factor kappa B (NF-κB) such as prostratin, show promising activity in reversing latency in vitro when used either alone or in combination. Alternate strategies include using gene therapy to modify expression of CCR5 and therefore make cells resistant to HIV. This review will primarily focus on the advantages and disadvantages of methods currently being used to quantify persistent virus ex vivo in patients receiving cART and strategies aimed at cure that are being tested in vitro or in early clinical development. In addition, we discuss key issues that need to be addressed to successfully move laboratory research to clinical trials aimed at curing HIV.
Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for ...HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers PTCs) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.
HIV infection can persist in spite of efficacious antiretroviral therapies. Although incomplete inhibition of viral replication may contribute to this phenomenon, this is largely due to the early ...establishment of a stable reservoir of latently infected cells. Thus, life-long antiviral therapy may be needed to control HIV. Such therapy is prone to drug resistance and cumulative side effects and is an unbearable financial burden for regions of the world hit hardest by the epidemic. This review discusses our current understanding of HIV persistence and the limitations of potential approaches to eradicate the virus and accordingly pleads for a joint multidisciplinary effort toward two highly related goals: the development of an HIV prophylactic vaccine and the achievement of long-term drug-free remissions in HIV-infected individuals.
The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and ...activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.
The main aim of this study was to determine whether HIV replication can be controlled following interruption of treatment started early in the course of infection (CD4 >350 cells/μl and viral load ...<50 000 copies/ml), but not during the primary infection.
Patients enrolled in a multicenter trial of treatment interruption (ANRS 116 SALTO) with CD4 above 450 cells/μl and viral load below 400 copies/ml at treatment interruption were selected for this second analysis. We determined the proportion of patients whose plasma HIV-RNA load remained below 400 copies/ml during the first 12 months of treatment interruption, and baseline factors predictive of time to loss of viral control. Viral load rebound was defined as two successive values above 400 copies/ml, or as one value above 400 copies/ml, followed by treatment resumption.
We studied 95 patients with a median CD4 nadir of 382 cells/μl (340-492). At treatment interruption, the median CD4 cell count and HIV-DNA load were 813/μl (695-988) and 206 copies/10 peripheral blood mononuclear cells (PBMCs) (53-556). Twelve months after treatment interruption, seven patients still had viral load below 400 copies/ml (Kaplan-Meier estimate 7.5%, 95% confidence interval 3.7-14.6), and four of them still had viral load below 400 copies/ml at 36 months. A multivariable Cox proportional-hazards model showed that time to loss of viral control was more shorter in patients with HIV-DNA at least 150 copies/10 PBMCs at treatment interruption (hazard ratio 2.1, 95% confidence interval 1.3-3.3, P = 0.002) than in those with HIV-DNA below 150 copies/10 PBMCs.
Patients who have low HIV-DNA levels at antiretroviral treatment interruption are more likely to maintain viral control for long periods.
Five out of 32 patients who received very early and prolonged antiretroviral therapy displayed an unusual, sustained immunovirological control after treatment discontinuation (mean duration: 77 ...months). These 'post-treatment controllers' did not have the genetic characteristics of spontaneous 'elite' controllers, although they shared very low and stable level of viral reservoir. Treatment may have dramatically decreased this reservoir and preserved potent HIV-specific immunologic responses, inducing a new balance between the virus and the host's immune system in these patients.
HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested ...to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac
-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8
T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.
HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a ...low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4(+) T cells and with less efficient virion production ex vivo We also found that a potent HIV-specific CD8(+) T cell response was present only in those HICs whose CD4(+) T cells produced virus ex vivo Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8(+) T cell response to counteract efficient viral reactivation events.
There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers HICs) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4(+) T cells in vitro were the most difficult were those with diminished CD8(+) T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.
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